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Aberrant p16INK4A and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma
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  1. A V Biankin1,
  2. S A Biankin2,
  3. J G Kench2,
  4. A L Morey3,
  5. C-S Lee4,
  6. D R Head5,
  7. R P Eckstein6,
  8. T B Hugh7,
  9. S M Henshall5,
  10. R L Sutherland5
  1. 1Cancer Research Program, Garvan Institute of Medical Research, and Division of Surgery, St Vincent's Hospital, Darlinghurst, NSW 2010 Australia
  2. 2Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2140, Australia
  3. 3Department of Anatomical Pathology, St Vincent's Hospital Campus, Darlinghurst, NSW 2010, Australia
  4. 4Department of Anatomical Pathology, Royal Prince Alfred Hospital, and Department of Pathology, University of Sydney, Camperdown, NSW 2050, Australia
  5. 5Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital Campus, Darlinghurst, NSW 2010, Australia
  6. 6Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
  7. 7Division of Surgery, St Vincent's Hospital Campus, Darlinghurst, NSW 2010, Australia
  1. Correspondence to:
    R L Sutherland, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St Darlinghurst, NSW 2010 Australia;
    r.sutherland{at}garvan.org.au

Abstract

Background and aims: Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor β/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT.

Methods: Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16INK4A, p21CIP1, p27KIP1, cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the χ2 and Fisher's exact tests.

Results: Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16INK4A expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p<0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p<0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p<0.001).

Conclusions: These data indicate that loss of p16INK4A and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.

  • intraductal papillary mucinous tumour
  • pancreatic adenocarcinoma
  • DPC4
  • Smad4
  • p53
  • p16
  • IPMT, intraductal papillary mucinous tumour
  • IPMC, intraductal papillary mucinous carcinoma
  • ERCP, endoscopic retrograde cholangiopancreatography
  • TGF-β, transforming growth factor β
  • Cdk, cyclin dependent kinase
  • pRb, retinoblastoma protein
  • PanIN, pancreatic intraepithelial neoplasia

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